In this prospective cohort of women undergoing infertility treatments, we measured specific-gravity adjusted urinary BPA (SG-BPA) concentrations and used regression models to evaluate the association of BPA with antral follicle count (AFC), day-3 serum follicle stimulating hormone levels (FSH), and ovarian volume (OV). BPA, detected in >80% of women, had a geometric mean (±GSD) of 1.6±2.0, 1.7±2.1, and 1.5±1.8μg/L for the women contributing to the AFC (n=154), day-3 FSH (n=120), and OV (n=114) analyses, respectively. There was an average decrease in AFC of 12% (95% CI: -23%, -0.6%), 22% (95% CI: -31%, -11%), and 17% (95% CI: -27%, -6%), in the 2nd, 3rd, and 4th SG-BPA quartile compared to the 1st quartile, respectively (p-trend: <0.001). No association of SG-BPA with FSH or OV was observed. Among women from an infertility clinic, higher urinary BPA concentrations were associated with lower AFC, raising concern for possible accelerated follicle loss and reproductive aging.

OBJECTIVE

An increased risk of depressive symptoms has been associated with the transition to menopause, but the risk of depressive symptoms in the early postmenopausal years has not been well characterized.

OBJECTIVE

To identify within-woman changes in depressive symptoms during a 14-year period around menopause, determine associations of a history of depression with the pattern of depressive symptoms, and evaluate the rate of change in reproductive hormones as predictors of depressive symptoms following menopause.

METHODS

A randomly identified, population-based sample in Philadelphia County, Pennsylvania, of 203 late-reproductive-age women who were premenopausal at baseline and reached natural menopause.

METHODS

Center for Epidemiologic Studies Depression Scale.

RESULTS

The prevalence of high scores on the Center for Epidemiologic Studies Depression Scale decreased from 10 years before to 8 years after the final menstrual period (FMP), with a decrease of approximately 15% of baseline per year (odds ratio, 0.85; 95% CI, 0.81-0.89; P < .001). Relative to the FMP, the risk of depressive symptoms was higher in the years before and lower in the years after the FMP. Among women with a history of depression, the likelihood of depressive symptoms was more than 13 times greater overall and 8 times greater after menopause compared with women with no depression history. Among women who first experienced depressive symptoms approaching menopause, the risk of depressive symptoms declined after the FMP, with a significantly lower risk the second year after menopause. The risk of depressive symptoms after menopause decreased by 35% for each unit (SD) increase before the FMP in the log rate of change of follicle-stimulating hormone (odds ratio, 0.65; 95% CI, 0.46-0.91; P = .01).

CONCLUSIONS

The FMP was pivotal in the overall pattern of decreasing depressive symptoms in midlife women, with higher risk before and lower risk after the FMP. A history of depression strongly increased the risk both before and after menopause. Women who had no history of depression before the menopause transition had a low risk of depressive symptoms 2 or more years after the FMP.

The aim of this study was to synthesize and present the latest available evidence regarding the use of oestrogen antagonists as empiric medical therapy for idiopathic male infertility with oligo and/or asthenoteratozoospermia through meta-analysis of randomized controlled trials (RCTs). Systematic literature acquisition was done for English and other foreign language biomedical databases up to March, 2013. RCTs relevant to the topic were identified and critically appraised independently by two physician reviewers. Dichotomous data of pregnancy rate and adverse events were extracted for calculation of odds ratio (OR) and 95% confidence interval (CI). Effect estimates were pooled using Peto method with fixed effect model. The continuous data of semen and endocrine parameters were calculated for the mean difference between pre- and post-treatment effects, the weighted mean difference (WMD) and SD between the control and intervention group were determined and pooled using the random effects model. Inter-study heterogeneity and publication bias were assessed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline for meta-analysis reporting was followed. Eleven RCTs of good methodological quality were included for meta-analysis. The pooled effect estimates showed that oestrogen antagonists use was associated with a statistically significant increased pregnancy rate compared with controls (pooled OR 2.42; 95% CI 1.47-3.94; p = 0.0004). Significant increase in sperm concentration (WMD 5.24; 95% CI 2.12, 88.37; p = 0.001) and per cent sperm motility (WMD 4.55; 95% CI 0.73, 8.37; p = 0.03) were also noted. While significant elevation of serum follicle stimulating hormone (WMD 4.19 95% CI 2.05, 6.34; p = 0.0001) and testosterone (WMD 54.59; 95% CI 15.92, 93.27; p = 0.006) was associated with its use. No significant difference in adverse event was noted between oestrogen antagonists-treated group and controls. The evidence suggests that oestrogen antagonists as empiric medical therapy for idiopathic male infertility with low non-serious adverse event associated, may increase spontaneous pregnancy rate, improve sperm concentration and per cent sperm motility.

The aim of our study was to investigate the relationships between the expression of leptin, leptin receptor in the testis and spermatogenesis, and testosterone (T) concentration in infertile men. Testicular tissue samples were collected from the testes of five fertile volunteers, eight patients with obstructive azoospermia (OA), six patients with Sertoli cell-only syndrome (SCO) and 32 oligospermic patients with varicocele testis. In testicular tissue, leptin and leptin receptor were identified by staining with polyclonal antibodies. Serum follicle stimulating hormone, lutenising hormone (LH), and T were determined by chemiluminescence assays. Leptin was expressed on germ cells, mainly on spermatocytes. The ratio of immunostained germ cells to total germ cells was inversely correlated with the concentration of T (r = -0.32, P = 0.01), sperm concentration (r = -0.51, P = 0.002) and Johnsen's score (r = -0.44,P = 0.005). In contrast, leptin receptor immunostained cells were found in the interstitium, primarily in Leydig cells. Leptin receptor expression on Leydig cells was inversely correlated with serum T concentration (r = -0.50, P < 0.001). The dysfunction of spermatogenesis is associated with an increase in leptin and leptin receptor expression in the testis.

To investigate the gonadal dysfunction and changes in sex hormones in male patients with postnecrotic cirrhosis, and to compare them with those in alcoholic cirrhotic men, three age-matched groups of men (hepatitis B virus-related postnecrotic cirrhosis 27, alcoholic cirrhosis 21, normal controls 30) were studied. Twelve of the 21 (57%) alcoholic cirrhotics and 16 of the 27 (59%) postnecrotic cirrhotics had a history of impotence. Both alcoholic and postnecrotic cirrhotic patients had significantly lower basal testosterone, but higher estradiol and prolactin levels than the control group (p less than 0.05). However, no differences were noted between the two cirrhotic groups. The degree of reduced testosterone and increased prolactin levels correlated with the severity of the cirrhosis. Despite the low testosterone concentration, basal levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were not increased in the cirrhotic patients. All the three groups studied had normal FSH and LH responses to the stimulation of exogenous gonadotropin releasing hormone. On the basis of these results, we conclude that: (1) impotence and low testosterone level are not infrequent findings in men with hepatitis B virus-related postnecrotic cirrhosis, especially in those with decompensated liver function. (2) The liver disease per se is important for the development of male sexual dysfunction. (3) The derangement of hypothalamic-pituitary function may play a role in the sexual dysfunction and changes in sex hormones in male patients with cirrhosis.

Ovarian hormones are biomarkers for breast cancer risk. Soybean consumption may be responsible in part for lower levels of ovarian hormones and decreased rates of breast cancer in women in Asia compared with Western populations. Soybeans contain a significant amount of the isoflavones daidzein and genistein, which are weak estrogens. The purpose of this study was to determine whether soya feeding decreases circulating levels of ovarian hormones and gonadotropins. Ten healthy, regularly cycling women consumed a constant soya-containing diet on a metabolic unit, starting on day 2 of a menstrual cycle until day 2 of the next cycle. Blood and urine samples were obtained daily for one menstrual cycle before and during soy feeding. The diet was calculated to maintain constant body weight, included 400 kilocalories from a 36-ounce portion of soymilk, and provided 113-207 mg/day (154.0+/-8.4 mg/day, mean +/- SE) of total isoflavones. For the group, the soya diet provided more carbohydrate and less protein than the home diets. Daily consumption of the soya diet reduced circulating levels of 17beta-estradiol by 25% (P<0.01, Wilcoxon signed rank test, two-tailed) and of progesterone by 45% (P<0.0001) compared with levels during the home diet period but had no effect on luteinizing hormone or follicle-stimulating hormone. Mean menstrual cycle length did not change during the soya diet; a slight decrease in mean luteal cycle length was marginally statistically significant (P = 0.06). Urinary excretion of isoflavones was 33.8+/-5.3 mg/day (mean +/- SE) and when expressed as percentage of intake, varied substantially (21.9+/-3.3% of intake; range, 9.1-36.7%) among the subjects. Mean daily serum levels of daidzein and genistein (free and conjugated forms) 15 h after soymilk were 2.89+/-0.53 microg/ml and 0.85+/-0.22 microg/ml, respectively, indicating systemic bioavailability of these substances. Secondary analyses by multiple regression showed that decreases in follicular and luteal phase 17beta-estradiol levels were positively associated with urinary isoflavone excretion, an association affected by age, and were inversely associated with decreases in protein intake. Decreases in progesterone levels during the soya diet were inversely associated with increases in intakes of genistein and were affected by the interaction of the intakes of daidzein with energy or with fiber. Consumption of an isoflavone-containing soya diet reduced levels of ovarian steroids in normal women over the entire menstrual cycle without affecting gonadotropins. This suggests that at least under the conditions of this study, soya-induced reductions of circulating ovarian steroids are not mediated by gonadotropins. Decreases in ovarian hormones are related to isoflavones contained in soy and also to energy intake and other components such as protein and fiber but not fat. Our results may explain decreased ovarian hormone levels and decreased risk of breast cancer in populations consuming soya diets and have implications for reducing breast cancer risk by dietary intervention.

An in vivo screening assay using intact adult male rats has been evaluated for its ability to detect six antiandrogenic compounds via oral administration. The test compounds included cyproterone acetate (CPA), flutamide (FLUT), p,p'-DDE (DDE), di-n-butyl phthalate (DBP), linuron (LIN), and vinclozolin (VCZ). Two of the test compounds (DDE and FLUT) have been previously evaluated in the 15-day intact male assay with compound administration via intraperitoneal injection (ip). For the current studies, male rats were dosed for 15 days via oral gavage and euthanized on the morning of test day 15. The endpoints evaluated included final body and organ weights (liver, thyroid gland, testes, epididymides, prostate, seminal vesicles with fluid, accessory sex gland unit [ASG]), serum hormone concentrations (testosterone [T], estradiol [E2], dihydrotestosterone [DHT], luteinizing hormone [LH], follicle stimulating hormone [FSH], prolactin [PRL], T(3), T(4), and thyroid stimulating hormone[TSH]), and histopathology of the testis, epididymis, and thyroid gland; positive results for each endpoint are described below. In addition, an evaluation of immune system endpoints (humoral immune function, spleen and thymus weights, and spleen cell number) was conducted on a subset of animals dosed with either DDE or FLUT. All six endocrine-active compounds (EACs) increased relative liver weight. FLUT and VCZ caused the typical pattern for an androgen receptor (AR) antagonist, although not all endpoints were statistically significant for VCZ: decreased ASG weights, hormonal alterations (increased T, DHT, LH, and FSH), and induced Leydig cell hypertrophy and/or hyperplasia. CPA caused effects consistent with its mixed AR antagonist/progesterone receptor agonist activity: it decreased ASG weights, caused hormonal alterations (increased T and E2; decreased FSH), and caused spermatid retention. DBP, a compound with antiandrogen-like activity via a nonreceptor mediated mechanism, caused hormonal alterations (decreased T, DHT, and E2; increased LH, FSH, and PRL) and induced general testicular degeneration. LIN, a weak AR antagonist, decreased ASG weights, caused hormonal alterations (decreased T, DHT, and LH; increased E2), and caused spermatid retention. Unlike the other AR antagonists evaluated, DDE, a weak AR antagonist, did not alter reproductive parameters. All six antiandrogens caused some effects on thyroid parameters, although only CPA, DDE, and VCZ caused results consistent with a potential thyroid-modulator. FLUT and DDE did not alter the primary humoral immune response to SRBC, spleen or thymus weights, or spleen cell number. In the current study, 5 of the six test substances were identified as endocrine-active substances consistent with their known/proposed mechanism(s) of action. The effects that were observed in the current study via oral (gavage) compound administration were similar to the responses that were observed by the ip route in previous studies for DDE and FLUT. This report, in addition to the>> 20 compounds that have already been examined using the 15-day intact male assay, supports this assay as a viable screening assay for detecting EACs, and also illustrates that the ability to identify EACs using the intact male assay will be equivalent regardless of the route of compound administration.

Transforming growth factor beta superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LbetaT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LbetaT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LbetaT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other's effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2's effects. In summary, BMPs regulate Fshb transcription in LbetaT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.

A combined test consisting of the simultaneous administration of insulin, thyrotrophin-releasing hormone (TRH), and luteinizing hormone and follicle stimulating hormone-releasing hormone (LH/FSH-RH) was performed in 24 people. Eleven of these also had the three individual tests performed separately, and the remaining 13 had a separate test of either LH/FSH-RH and TRH together or singly at a later date. In both normal people and patients, whether the tests were performed alone or in combination, no difference was found between the hormone responses (growth hormone, cortisol, LH, FSH, thyroid-stimulating hormone) seen to these stimuli.It is proposed that combined administration of insulin and the hypothalamic releasing hormones may be used as a single test for the assessment of anterior pituitary function. The test is convenient and time saving, and with care can be performed in outpatients.

OBJECTIVE

To investigate the effectiveness of minidose GnRH agonist (GnRH-a) + hMG in poor responders with elevated basal level FSH.

METHODS

Retrospective analysis of IVF cycles.

METHODS

IVF Unit, Golda Medical Center, Petah Tikva, Israel.

METHODS

One hundred six patients who were defined as poor responders on two previous IVF attempts. Three treatment protocols of midluteal Decapeptyl (D-Trp6) were compared: [1] a single-dose of 3.75 mg; [2] 0.5 mg daily until menstruation, followed by 0.1 mg daily; and [3] 0.1 mg daily until menstruation, followed by 0.05 mg daily.

METHODS

Comparisons were made among the three protocols regarding basal FSH levels, number of oocytes retrieved and fertilized, number of days of stimulation, follicular phase, P levels, and pregnancy and miscarriage rates.

RESULTS

Treatment with minidose GnRH-a resulted in higher E2 levels and lower P levels on the day of hCG and lower cancellation rates. Furthermore, a higher number of oocytes recovered and fertilized and embryos transferred were recorded. The trend indicated improved pregnancy and implantation rates with a lower miscarriage rate.

CONCLUSIONS

Minidose GnRH-a is a better choice than regular GnRH-a strategies in poor-responder patients undergoing IVF treatment.

Patients with severe thalassaemia major suffer endocrine and other abnormalities before their eventual death from iron overload due to repeated blood transfusions. The endocrine status of 31 thalassaemic patients aged 2-5 to 23 years was investigated. Exact data were available on the rate and duration of blood transfusion in all of them and in many the liver iron concentration was also known. Although the patients were euthyroid, the mean serum thyroxine level was significantly lower, and the mean thyrotrophic hormone level significantly higher, compared with the values found in normal children. Forty oral glucose tolerance tests with simultaneous insulin levels were performed in 19 children, of whom 5 developed symptomatic diabetes and one had impaired tolerance. Previous tests on all 6 patients were available and some showed raised insulin levels possibly due to insulin resistance. 2 patients had clinical hypoparathyroidism and are described. The parathyroid hormone levels determined by radioimmunoassay in 25 patients were below the mean for the age group in all and outside the reference range in 16. Nonfasting plasma calcium levels were not reduced. Puberty was delayed in some patients. Concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) measured in urine from 7 girls and 5 boys showed considerable variation. In the boys there was an overall tendency for FSH and LH excretion to be low with regard to age, but with respect to puberty rating FSH exretions were normal or low and LH normal or raised. The girls showed a tendency for LH but not FSH excretion to be raised in relation to puberty rating. The severity of the endocrine changes was related to the degree of iron loading and is discussed in relation to previous work in which the iron loading has rarely been accurately indicated nor parathyroid status assessed.

The role of the suprachiasmatic nuclei (SCN) in the response to short-day melatonin (MEL) signals was examined in long-day-housed pinealectomized (PINX) Siberian hamsters. Five- or ten-hour MEL infusions that mimicked the peak nocturnal durations of serum MEL levels in long or short days, respectively, or control saline infusions were given for 5 wk. Half the hamsters in each infusion group also received bilateral electrolytic SCN lesions. The 10-h MEL infusions reduced testes weight, body and fat pad weights, and serum prolactin (PRL) and follicle-stimulating hormone (FSH) concentrations in unoperated controls. These short-day-type effects were blocked by SCN lesions, which often produced hyperprolactinemia. Circadian rhythms of locomotor activity were disrupted or sparse in hamsters with lesions in or near the SCN. In a second experiment, 5 wk of long-day-like, short-duration (5-h) MEL infusions were administered to hamsters that had been PINX after 8 wk of short-day exposure. Control hamsters given 5-h MEL infusions, but not 10-h MEL or saline infusions, exhibited testicular growth and increased serum PRL levels. Hamsters with SCN lesions showed similar responses, regardless of the duration or type of infusion. Although the blockade of 10-h MEL infusion-induced testicular regression by SCN lesions in experiment 1 may have been due to stimulation of the testes by PRL, it is unlikely that the hyperprolactinemia accounted for the ability of SCN lesions to block effects of 10-h MEL infusions on fat pad and body weights. Therefore, the SCN and/or neighboring structures may participate in the response to short-day MEL signals in Siberian hamsters.

OBJECTIVE

To assess the efficacy of gonadotropin-releasing hormone agonist (GnRHa) in preventing chemotherapy-induced ovarian failure in patients treated for Hodgkin or non-Hodgkin lymphoma within the setting of a multicenter, randomized, prospective trial.

METHODS

Patients age 18 to 45 years were randomly assigned to receive either the GnRHa triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) concomitantly with alkylating agents containing chemotherapy. The primary end point was the premature ovarian failure (POF) rate (follicle-stimulating hormone [FSH] ≥ 40 IU/L) after 1 year of follow-up.

RESULTS

Eighty-four of 129 randomly assigned patients completed the 1-year follow-up. The mean FSH values were higher in the control group than in the GnRHa group during chemotherapy; however, this difference was no longer observed after 6 months of follow-up. After 1 year, 20% and 19% of patients in the GnRHa and control groups, respectively, exhibited POF (P = 1.00). More than half of patients in each group completely restored their ovarian function (FSH < 10 IU/L), but the anti-Müllerian hormone values were higher in the GnRHa group than in the control group (1.4 ± 0.35 v 0.5 ± 0.15 ng/mL, respectively; P = .040). The occurrence of adverse events was similar in both groups with the exception of metrorrhagia, which was more frequently observed in the control group than the GnRHa group (38.4% v 15.6%, respectively; P = .024).

CONCLUSIONS

Approximately 20% of patients in both groups exhibited POF after 1 year of follow-up. Triptorelin was not associated with a significant decreased risk of POF in young patients treated for lymphoma but may provide protection of the ovarian reserve.

OBJECTIVE

To investigate effect of sperm DNA fragmentation (SDF) on clinical outcomes of assisted reproductive technology in women with normal ovarian reserve (NOR) versus reduced ovarian reserve (ROR).

METHODS

Retrospective clinical study.

METHODS

University-affiliated tertiary teaching hospital.

METHODS

A total of 2,865 consecutive couples undergoing their first in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

METHODS

SDF assessed using sperm chromatin dispersion in sperm samples 1-2 months before treatment.

METHODS

SDF, IVF, and ICSI outcomes.

RESULTS

The grouping criteria were [1] basal follicle stimulating hormone >10 IU/L, [2] antral follicle count <6, and [3] female age ≥38 years. Women fulfilling two of the three criteria were considered to have ROR, and those not meeting any criteria were considered to have NOR. The area under the receiver operating characteristic curve was 0.594 (0.539-0.648) for the ROR group and 0.510 (0.491-0.530) for the NOR group. A cutoff value for SDF to predict the clinical pregnancy rate (CPR) in the ROR group was 27.3%. When the SDF exceeded 27.3%, the live-birth and implantation rates in the ROR group were statistically significantly decreased, but the clinical pregnancy, live-birth, and implantation rates were not affected in the NOR group. The risk of early abortion increased significantly in the NOR group when the SDF exceeded 27.3%.

CONCLUSIONS

Sperm DNA fragmentation has a greater impact on IVF and ICSI outcomes among women with ROR, so SDF testing may be of particular clinical significance for these couples.

Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and metabolism primarily of cells of mesenchymal origin. In this study, we found high levels of PDGFs and PDGFs receptors (PDGFRs) mRNAs, and specific immunostaining for the corresponding proteins in the rat testis. PDGFs and PDGFRs expression was shown to be developmentally regulated and tissue specific. Expression of PDGFs and PDGFRs genes was observed in whole testis RNA 2 d before birth, increased through postnatal day 5 and fell to low levels in adult. The predominant cell population expressing transcripts of the PDGFs and PDGFRs genes during prenatal and early postnatal periods were Sertoli cells and peritubular myoid cells (PMC) or their precursors, respectively, while in adult animals PDGFs and PDGFRs were confined in Leydig cells. We also found that early postnatal Sertoli cells produce PDGF-like substances and that this production is inhibited dose dependently by follicle-stimulating hormone (FSH). The expression of PDGFRs by PMC and of PDGFs by Sertoli cells corresponds in temporal sequence to the developmental period of PMC proliferation and migration from the interstitium to the peritubulum. Moreover, we observed that all the PDGF isoforms and the medium conditioned by early postnatal Sertoli cells show a strong chemotactic activity for PMC which is inhibited by anti-PDGF antibodies. These data indicate that, through the spatiotemporal pattern of PDGF ligands and receptors expression, PDGF may play a role in testicular development and homeostasis.

OBJECTIVE

To examine the use of the aromatase inhibitor letrozole with FSH for ovarian stimulation in poor responders undergoing ovarian superovulation and IUI.

METHODS

Observational cohort study as a prospective clinical trial in patients with unexplained infertility and a low response to ovarian stimulation with FSH.

METHODS

Two tertiary referral infertility clinics associated with the Reproductive Sciences Division, University of Toronto.

METHODS

Twelve patients with unexplained infertility undergoing IUI who received FSH alone in 25 prior cycles with poor response (less than three dominant follicles).

METHODS

Patients were offered letrozole, 2.5 mg/day from day 3-7 of the menstrual cycle with FSH (50-225 IU/day) starting on day 5-7. hCG (10,000 IU) was given when two leading follicles were>>/=2 cm followed by IUI.

METHODS

Number of mature follicles (>1.8 cm), FSH dose, endometrial thickness, and pregnancy rate.

RESULTS

Improved response to FSH stimulation with letrozole co-treatment was evidenced by the significantly lower FSH dose associated with significantly higher number of mature follicles. During letrozole plus FSH stimulation cycles, clinical pregnancy was achieved in three cycles (21%).

CONCLUSIONS

In this preliminary report, we demonstrate a potential benefit of aromatase inhibition for improving ovarian response to FSH in poor responders.

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

A prospective, randomized, comparative, assessor-blind study was carried out in two centres to compare the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH; Gonal-F) versus highly purified urinary FSH (u-hFSH HP; Metrodin HP), both administered s.c. in women undergoing ovarian stimulation for in-vitro fertilization including intracytoplasmic sperm injection (ICSI). A total of 235 patients started a long gonadotrophin-releasing hormone agonist protocol: 119 received r-hFSH and 114 received u-hFSH HP (150 IU/day) for the first 6 days. Two patients were excluded from the study because they mistakenly received the incorrect treatment combination. Human chorionic gonadotrophin (HCG; 10000 IU, s.c.) was administered once there was at least one follicle 18 mm in diameter and two others>> or = 16 mm. In all, 119 (100%) and 102 (89%) of the patients respectively in the r-hFSH and u-hFSH HP groups achieved the criteria for HCG. The mean numbers (+/- SD) of oocytes recovered (the primary endpoint) were 12.2 +/- 5.5 and 7.6 +/- 4.4 in the r-hFSH and u-hFSH HP groups respectively (P < 0.0001). However, the number of FSH treatment days (11.0 +/- 1.6 versus 13.5 +/- 3.7) and the number of 75 IU ampoules (21.9 +/- 5.1 versus 31.9 +/- 13.4) used were significantly less (P < 0.0001) in the r-hFSH group than in the u-hFSH HP group. In patients treated using ICSI (63 patients in each group), no difference in oocyte maturation was observed. The mean numbers of embryos obtained were 8.1 +/- 4.2 and 4.7 +/- 3.5 (P < 0.0001), in favour of the r-hFSH group. In the majority of patients (96 and 99% respectively) only one or two embryos were replaced (mean 2.0 +/- 0.2 and 1.9 +/- 0.1 respectively) in the r-hFSH and u-hFSH HP groups. The clinical pregnancy rates per started cycle and per embryo transfer were 45 and 36%, and 48 and 47%, respectively in the r-hFSH and u-hFSH HP groups (not significant). There were six (5.1%) and two (1.7%) cases of ovarian hyperstimulation syndrome respectively. In conclusion, it was found that r-hFSH was more effective than u-hFSH at inducing multiple follicular development. However, the high rate of low ovarian response in the u-hFSH group compared with our general experience was unexpected. The availability of a gonadotrophin with less inter-batch variation would be beneficial for clinicians. r-hFSH seems to fulfil such a requirement.

To assess more closely the physiological mechanism(s) by which ethanol (ETOH) delays the onset of female puberty, we have evaluated its effects on body weight, the vaginal opening (VO)-first diestrus (D1) interval and the serum concentrations of growth hormone (GH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) throughout the peripubertal period in the rat. Using a specific intragastric feeding regimen, 29-day-old rats began receiving either a liquid diet containing ETOH or an isocaloric control liquid diet. Additional controls consisted of animals maintained on laboratory chow and water provided ad libitum. Animals were either killed between 32 and 37 days of age, categorized with regard to their phase of puberty and their serum hormones measured; or, in some animals, the ETOH liquid diet was administered through day 41 and at that time replaced by the control liquid diet in order to determine if recovery would occur. Our results indicate that ETOH-treated animals showed significantly lower body weights and a significantly longer mean VO-D1 interval than the control animals. Also, serum GH and LH levels were significantly lower in the ETOH-treated animals; however, FSH levels were not affected. Administration of the ETOH liquid diet through day 41 produced varying detrimental effects on the onset of puberty and subsequent removal of ETOH from the diet resulted in rapid growth of the animals, followed by the onset of puberty.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

By one estimate, 60% of women experiencing the menopause transition perceive that they have memory problems, but most studies that have used cognitive function tests have not substantiated a relation between menopause stage and cognitive performance. We sought to describe the cross-sectional relation between menopause status, estradiol (E(2)), follicle-stimulating hormone (FSH), and measured cognitive function.

METHODS

Cross sectional analysis of a community-based cohort of midlife women was used. Cognitive tests were the East Boston Memory Test, Symbol Digit Modalities, and Digits Span Backward. Menopause categories (premenopausal, early perimenopausal, late perimenopausal, and postmenopausal) were defined based on menstrual patterns. One set of general linear models assessed the relations between each cognitive test and menopause transition category, initially adjusted for age, race/ethnicity, education, symptoms, self-rated general health, and body mass index (BMI); next, these were additionally adjusted for FSH and E(2). A second set of models, stratified by menopause status, examined the possible relations between each cognitive test and either E(2) or FSH, adjusted for age, race/ethnicity, education, symptoms, self-related general health, and BMI.

RESULTS

The mean age of the analytical sample (n = 1657) was 49.7 years. Only 5% of the sample had less than a high school education, 16% graduated from high school, and the rest had at least some college. The percent of women in each menopause category was premenopausal (9.0%), early perimenopausal (57.0%), late perimenopausal (13.4%), postmenopausal (20.6%). Although clinical-site adjusted models showed moderate differences between menopause transition groups and cognitive performance, no association was found between each of the measured cognitive performance tests and menopause transition status when adjusting for covariates. Similarly, no association between each cognitive test and E(2) or FSH was found.

CONCLUSIONS

This study does not support a cross-sectional relation between cognitive test performance and menopause stage, FSH, or E(2).

The temporal relationship between LHRH release and gonadotropin secretion as well as the effects of castration on LHRH release were investigated in conscious, freely moving male rats. LHRH release was measured in hypothalamic/median eminence perfusates, while levels of pituitary gonadotropins (LH, FSH) were determined in sequential blood samples obtained via atrial catheters. Twenty-four to 26 h before experiments, rats underwent sham surgery or castration. LHRH release in push-pull perfusates from both groups was pulsatile, and nearly all identified LH pulses (83.3%) were temporally associated with LHRH pulses. Of the fewer irregular FSH pulses that were observed, only 43.7% were temporally associated with LHRH pulses. Mean LHRH pulse amplitude and mean LHRH levels were not different in intact and castrate animals. The frequency of LHRH pulses was moderately increased in castrate rats (1.30 pulses/h) compared to that in intact animals (0.83 pulses/h), and this acceleration was accompanied by a significant increase in LH pulse frequency, pulse amplitude, and mean level. It was also noted that the number of silent LHRH pulses (those not associated with LH pulses) was dramatically reduced in castrate animals. Characteristics of gonadotropin release (pulse frequency, pulse amplitude, and mean level) were not significantly different in animals undergoing push-pull perfusion/bleeding procedures from those in rats not receiving push-pull cannula implants. We conclude from these studies that 1) LH pulses show a high concordance with LHRH pulses, providing evidence that the LHRH pulse generator operates as the neural determinant of LH pulses in male rats, 2) FSH secretion is not associated with LHRH release in an obvious and consistent manner, suggesting that LHRH/FSH relationships are not easily discerned in these animals or that a FSH-releasing factor distinct from the LHRH decapeptide may regulate FSH secretion, 3) a modest increase in LHRH pulse frequency occurs 24-30 h after castration, and 4) silent LHRH pulses occur with much greater regularity in intact than in castrate rats. The latter two observations suggest that both hypothalamic and intrapituitary sequelae of castration may be critically important in the development of postcastration increases in LH secretion and the negative feedback of gonadal steroids.

Preantral follicles of cyclic hamsters were isolated on proestrus, estrus and diestrus I, incubated for 3 h in 1 ml TC-199 containing 1 microgram ovine luteinizing hormone (LH) (NIH-S22), and the concentrations of progesterone (P), androstenedione (A) and estradiol (E2) determined by radioimmunoassay. At 0900-1000 h on proestrus (pre-LH surge) preantral follicles produced 2.4 +/- 0.3 ng A/follicle per 3 h, less than 100 pg E2/follicle and less than 250 pg P/follicle. At the peak of the LH surge (1500-1600 h) preantral follicles produced 1.8 +/- 0.2 ng P and 1.9 +/- 0.1 A and less than 100 pg E2/follicle. After the LH surge (1900-2000 h proestrus and 0900-1000 h estrus) preantral follicles were unable to produce A and E2 but produced 4.0 +/- 1.0 and 5.0 +/- 1.1 ng P/follicle, respectively. By 1500-1600 h estrus, the follicles produced 8.1 +/- 3.1 ng P/follicle but synthesized A (1.6 +/- 0.2 ng/follicle) and E2 (362 +/- 98 pg/follicle). On diestrus 1 (0900-1000 h), the large preantral-early antral follicles produced 1.9 +/- 0.3 ng A, 2.4 +/- 0.4 ng E2 and 0.7 +/- 0.2 ng P/follicle. Thus, there was a shift in steroidogenesis by preantral follicles from A to P coincident with the LH surge; then, a shift from P to A to E2 after the LH surge. The LH/follicle-stimulating hormone (FSH) surges were blocked by administration of 6.5 mg phenobarbital (PB)/100 g BW at 1300 h proestrus. On Day 1 of delay (0900-1000 h) these follicles produced large quantities of A (2.2 +/- 0.2 ng/follicle) and small amounts of E2 (273 +/- 27 pg/follicle) but not P (less than 250 pg/follicle).(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal integration of the reproductive system is dramatically affected by reproductive aging. The progressive loss of ovarian follicles with normal aging is accompanied by an initial decrease in inhibin B and a concomitant increase in follicle-stimulating hormone. Subsequently, inhibin A and progesterone decrease, where as estradiol levels are maintained and often increase. In the late reproductive stage, cycles remain regular whereas the early and late menopausal transition are characterized by irregular cycles and often dramatic swings in estradiol and gonadotropin levels. Studies in younger and older postmenopausal women suggest that there are age-related changes in the neuroendocrine axis that are independent of the changing ovarian hormonal milieu of the menopausal transition but may contribute to the end of reproductive life.

GnRH regulates gonadotrope cells through GnRH receptor activation of the PKC-, MAPK-, and calcium-activated signaling cascades. Due to the paucity of homologous model systems expressing FSHbeta, little is known about the specific mechanisms involved in transcriptional regulation of this gene by GnRH. Previous studies from our laboratory demonstrated that the gonadotrope-derived LbetaT2 cell line expresses FSHbeta mRNA. In the present study we characterized the mechanisms involved in GnRH regulation of the FSHbeta promoter using this cell model. Using transfection assays, we show that GnRH regulation of the ovine FSHbeta promoter involves at least two elements, present between -4152/-2878 and -2550/-1089 bp, in association with one or several elements within the proximal region of the promoter. Surprisingly, the two activating protein-1 sites previously shown to be involved in the FSHbeta response to GnRH in heterologous cells do not play a role in GnRH responsiveness in the gonadotrope cell model. Here we demonstrate that calcium influx itself is not sufficient to confer the response, but it is necessary for both 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and GnRH induction of the FSHbeta gene. Moreover, we show that GnRH regulation of FSHbeta gene expression is mediated by PKC and establish the presence of multiple PKC isozymes in LbetaT2 cells. Interestingly, GnRH and TPA induce activity of the FSHbeta promoter through different, although possibly overlapping, pools of PKC isoforms. This is further supported by the use of a MAPK inhibitor, which abolishes the induction of FSHbeta by GnRH, but not by TPA. In conclusion, we have demonstrated that calcium, PKC, and MAPK signaling systems are all involved in the induction of FSHbeta gene expression by GnRH in the LbetaT2 mouse gonadotrope cell model.